Noxious chemical, thermal and mechanical stimuli excite peripheral nerve endings of small diameter sensory neurons (nociceptors) deriving from sensory ganglia (e.g., dorsal root, nodose and trigeminal ganglia) and initiate signals that are perceived as pain. Such nociceptive neurons (i.e., nociceptors) are crucial for the detection of harmful or potentially harmful stimuli (e.g., noxious thermal, chemical, and/or mechanical) that arise from changes in the extracellular environment during inflammatory, ischemic or otherwise traumatic conditions and that cause or have the potential to cause tissue damage (Wall, P. D., and Melzack, R., Textbook of Pain, 1994, New York: Churchill Livingstone).
Nociceptors transduce noxious stimuli into membrane depolarization that leads to an action potential, its subsequent conduction to the CNS, and ultimately to the perception of pain, discomfort, etc. as well as to certain responses thereto. At the molecular level, nociception is carried out by ion channels and/or receptors. Plant-derived vanilloid compounds (e.g., capsaicin and resiniferatoxin) are known to selectively depolarize nociceptors and elicit sensations of burning pain: the sensation that is typically evoked by capsaicin-containing hot chili peppers. Therefore, capsaicin mimics the action of physiological/endogenous stimuli that activate the “nociceptive pathway”. Recent advances in pain biology have identified a receptor, called VR1 (a.k.a. capsaicin receptor or TRPV1) for vanilloids, protons and noxious heat. Because nociceptors are drivers of unwanted pain and inflammatory conditions in human beings and animals, modulation of their function is a validated strategy for palliative and other analgesic therapies.
Compounds that are modulators (competitive and non-competitive agonists or antagonists [with respect to capsaicin and/or its recognition site] and allosteric modulators) at VR1 have broad therapeutic potential, as demonstrated by the clinical usefulness of marketed, VR1-targeted pharmaceutical agents or the efficacy of VR1 modulators in animal models of disease. Furthermore, it is recognized that agonist modulators of VR1 may possess clinical utility deriving from their agonist properties, per se, and/or from their ability to produce an agonist-mediated desensitization, which would indirectly manifest as a functional antagonism. Similarly, antagonist modulators could exhibit direct antagonist (competitive or non-competitive) properties and/or indirect antagonist properties via the aforementioned desensitization mechanism. It is further recognized that positive and negative allosteric modulators may produce any or all of the aforementioned functional consequences and, as such, may also have clinical utility. Accordingly, this invention is directed to each of these types of modulators.
The effective use of VR1 agonists has been demonstrated in inflammatory, neuropathic, and visceral pain states. In an experimental human pain model, dermal capsaicin pretreatment reduced the pain caused by intradermal injection of an acidic solution (Bianco, E. D.; Geppetti, P.; Zippi, P.; Isolani, D.; Magini, B.; Cappugi, P. Brit J of Clin Pharmacol 1996, 41, 1-6), suggesting the benefit of VR1 agonists in the treatment of inflammatory pain. A particular role for VR1 agonists has been shown in inflammation and inflammatory pain: for example, resiniferatoxin prevented inflammatory hypersensitivity and edema induction by carrageenan (Kissin, I.; Bright, C. A.; Bradley, E. L., Jr. Anesth Analg 2002, 94, 1253-1258).
Additionally, capsaicin-containing creams (for example, Axcain® and Lidocare®) are marketed for dermal relief of pain related to diabetic neuropathy and postherpetic neuralgia, indicative of the usefulness of VR1 agonists in the treatment of neuropathic pain states. Furthermore, such creams have been shown to reduce postsurgical neuropathic pain (Ellison, N., Loprinzi, C. L., Kugler, J., Hatfield, A. K., Miser, A., Sloan, J. A., Wender, D. B., Rowland, K. M., Molina, R., Cascino, T. L., Vukov, A. M., Dhaliwal, H. S. and Ghosh, C. J. Clin. Oncol. 15:2974-2980, 1997). In cancer patients, capsaicin contained in a taffy vehicle, was shown to substantially reduce oral mucositis pain caused by chemotherapy and radiation therapy (Berger, A., Henderson, M., Naadoolman, W., Duffy, V., Cooper, D., Saberski, L. and Bartoshuk, L. J. Pain Sympt. Mgmt 10:243-248, 1995.
VR1 also plays a role in the physiology of bladder emptying. VR1 is expressed by bladder sensory neurons, where it modulates bladder responsivity to liquid filling. The VR1 agonist resiniferatoxin desensitized bladder afferents in a dose-dependent manner (Avelino, A.; Cruz, F.; Coimbra, A. Eur. J Pharmacol. 1999, 378, 17-22), supporting its usefulness for the treatment of overactive bladder (Chancellor, M. B.; De Groat, W. C. J. Urol. (Baltimore) 1999, 162, 3-11). Indeed, intravesicular administration of capsaicin or resiniferatoxin inhibited bladder contraction in both normal and spinal cord injured rats (Komiyama, I.; Igawa, Y.; Ishizuka, O.; Nishizawa, O.; Andersson, K.-E. J. Urol. (Baltimore) 1999, 161, 314-319), indicative of the usefulness of VR1 agonists in nerve-injured incontinent patients. The effectiveness of capsaicin or resiniferatoxin treatment on incontinence in spinal cord injured patients was confirmed in a clinical study (de Seze, M.; Wiart, L.; de Seze, M.-P.; Soyeur, L.; Dosque, J.-P.; Blajezewski, S.; Moore, N.; Brochet, B.; Mazaux, J.-M.; Barat, M.; Joseph, P.-A. Journal of Urology (Hagerstown, Md., United States) 2003, 171, 251-255).
The effectiveness of VR1 agonists in the reduction of elevated blood pressure is suggested by capsaicin reduction in blood pressure in SHR and WKY rats (Li, J.; Kaminski, N. E.; Wang, D. H. Hypertension 2003, 41, 757-762.). Capsaicin was also gastroprotective with respect to gastric antral ulcers (Yamamoto, H.; Horie, S.; Uchida, M.; Tsuchiya, S.; Murayama, T.; Watanabe, K. Eur. J. Pharmacol. 2001, 432, 203-210).
VR1 antagonists also may be useful in the treatment of inflammatory, neuropathic and visceral pain. For example, the therapeutic utility of VR1 antagonists has been demonstrated in visceral inflammatory conditions. VR1 is elevated in colonic nerve fibers in patients with inflammatory bowel disease, and VR1 antagonists relieved pain and dysmotility (Yiangou, Y.; Facer, P.; Dyer, N. H.; Chan, C. L.; Knowles, C.; Williams, N. S.; Anand, P. Lancet 2001, 357, 1338-1339). Intestinal inflammation induced by toxin A or dextran sulfate sodium in rodents was attenuated by VR1 antagonists (McVey, D. C.; Schmid, P. C.; Schmid, H. H. O.; Vigna, S. R. J. Pharmacol. Exp. Ther. 2003, 304, 713-722). In addition, a synthetic VR1 antagonist reduced colitis disease scores at several important endpoints, including macroscopic damage, microscopic epithelial damage, myeloperoxidase levels, and diarrhea scores, strongly supporting the therapeutic use of VR1 antagonists in inflammatory bowel diseases (Kimball, E. S.; Wallace, N. H.; Schneider, C. R.; D'Andrea, M. R.; Hornby, P. J. Neurogasteroenterology 2004, 16, 811-818). The VR1 antagonists capsazepine and BCTC reversed mechanical hyperalgesia in models of inflammatory and neuropathic pain in guinea pigs (Walker, K. M.; Urban, L.; Medhurst, S. J.; Patel, S.; Panesar, M.; Fox, A. J.; McIntyre, P. J. Pharmacol. Exp. Ther. 2003, 304, 56-62) and rats (Pomonis, J. D.; Harrison, J. E.; Mark, L.; Bristol, D. R.; Valenzano, K. J.; Walker, K. J. Pharmacol. Exp. Ther. 2003, 306, 387-393).
LPS-induced fever was attenuated in VR1 knock out mice (Lida, T.; Shimizu, I.; Nealen, M. L.; Campbell, A.; Caterina, M. Neurosci. Lett. 2005, 378, 28-33). VR1 agonist-induced rises in core body temperature were suppressed by capsazepine, indicative of the usefulness of VR1 antagonists in the treatment of pyresis (Ohnluki, K.; Haramizu, S.; Watanabe, T.; Yazawa, S.; Fushiki, T. J. Nutr. Sci. Vitaminol. (Tokyo) 2001, 47, 295-298).
VR1 agonists also modulate body temperature and fever. In ferret, rat and mouse, administration of resiniferatoxin-induced hypothermia (Woods, A. J.; Stock, M. J.; Gupta, A. N.; Wong, T. T. L.; Andrews, P. L. R. Eur. J. Pharmacol. 1994, 264, 125-133). Additionally, phase I of LPS (lipopolysaccharide)-induced fever did not occur in animals desensitized with low intraperitoneal doses of capsaicin (Romanovsky, A. A. Frontiers in Bioscience 2004, 9, 494-504).
The therapeutic potential of VR1 antagonists in inflammatory bronchial conditions is demonstrated by the finding that they antagonize capsaicin- and acid-induced bronchoconstriction (Nault, M. A.; Vincent, S. G.; Fisher, J. T. J. Physiol. 1999, 515, 567-578). Related findings demonstrate that the VR1 antagonist capsazepine attenuates anandamide-induced cough in guinea pigs (Jia, Y.; McLeod, R. L.; Wang, X.; Parra, L. E.; Egan, R. W.; Hey, J. A. Brit. J. Pharmacol. 2002, 137, 831-836).
The VR1 antagonist capsazepine was demonstrated to significantly reduce anxiety-like behaviors in rats using the elevated plus maze (Kasckow, J. W.; Mulchahey, J. J.; Geracioti, T. D. Jr. Progress in Neuro-Psychopharmacol. and Biological Psychiatry 2004, 28, 291-295). Thus, VR1 antagonists may have utility in the treatment of anxiety, panic disorders, phobias or other non-adaptive stress responses.
U.S. Pat. No. 6,299,796B1 discloses electroluminescent elements comprising units of the formula:

Thus, there is a need for potent modulators of VR1, and in particular, for novel benzimidazole compounds that exhibit potent binding affinity for the human and rat VR1 ion channel. There is also a need for novel benzimidazole compounds that act as potent functional antagonists and/or agonists of the human and rat VR1 ion channel. Finally, there is a need for novel benzimidazoles that bind with high affinity to VR1 and also act as potent functional antagonists of the human and rat VR1 ion channel.